DESCRIPTION: (PI's abstract) This application is submitted in response to PAS 99-080, "Exploratory Grants in Pediatric Brain Disorders: Integrating the Science." The proposal will lay the foundation for a new inter-institutional collaboration (Univ. Of Michigan and Wayne State Univ.) between clinician scientists with expertise in the pathogenesis of brain injury (Drs. Silverstein and Barks), and a neuroanatomist with expertise in oligodendroglial development (Dr. Skoff). The long-term goal of the proposed research is to develop novel approaches for understanding the pathogenesis of hypoxic-ischemic white matter injury in the immature brain. Studies of neonatal ischemic brain injury in experimental models have focused on mechanisms of neuronal injury and neuroprotection, and have largely neglected white matter injury. Yet, in human neonates and young infants the white matter, particularly in periventricular regions, is highly susceptible tp ischemic injury. In preliminary experiments, in situ hybridization and RT-PCR assays were developed to examine injury-induced changes in expression of 2 oligodendroglia (OL)-specific genes, proteolipid protein (PLP), and myelin basic protein (MBP); preliminary findings provide the impetus for this application. Experiments performed in immature rodent stroke models (in neonatal rats and mice) revealed that hypoxic ischemic injury results in acute disruption of OL gene expression within periventricular white matter; and also alters expression of OL-specific genes in cells in the sub-ventricular zone; in neonatal rats, intraventricular injection of the excitatory amino acid agonist AMPA results in a similar pattern of acute disruption of OL gene expression. This application proposes to build upon these finding to develop novel approaches for understanding mechanisms of OL injury in the immature brain. Aim 1 will: evaluate the influence of hypoxia-ischemia (HI) on PLP and MBP gene expression; determine whether acute HI induced suppression of OL-gene expression predicts the severity of chronic OL damage; and evaluate the impact of specific interventions that could exacerbate or attenuate HI-induced OL injury. Aim 2 will examine the influence of AMPA lesioning on PLP and MBP gene expression and OL injury. Aim 3 focuses upon the impact of HI on OL precursors in the ventricular and subventricular zones; and specifically will analyze whether these OL precursors undergo apoptosis, whether the loss of OL precursors is permanent, and whether mild HI insults can elicit a proliferative response in these cells. Taken together, results of these experiments will improve our understanding of the impact of HI on OL in the immature brain and enhance development of more effective therapeutic approaches to limit or prevent neonatal ischemic white matter injury.